DESCRIPTION: The central hypothesis of this proposal is that the formation of a gp120-CD4-coreceptor complex (tricomplex) induces conformational and specific epitope rearrangements on one or more of the three complex components. It also hypothesizes that these conformational changes are directly involved in the subsequent exposure of the N-terminal domain of gp41 and its insertion into the target cell membrane. Thus, monoclonal antibodies which are specific for the trimolecular complex have high probability of blocking the fusion process. The isolation of these antibodies and the characterization of their epitopes may be useful in the development of vaccine and therapeutic strategies against HIV-1 infection. The specific aims of the proposal are: 1) To determine whether cryptic epitopes are exposed on the components of a tripartate complex of gp120-CD4-coreceptor. 2) To determine whether monoclonal antibodies specific for gp120-CD4-coreceptor complexes neutralize gp120. The immunogens for these studies will be cross-linked tripartate complexes formed on the surface of murine cells expressing either CCR5 or CXCR4 coreceptors. The gp120 will be derived from T-tropic (IIIB) or M-tropic (Ba-L) strains. In addition, an oligomeric gp160 form of a T-tropic envelope (451) will be used. These envelope proteins will be complexed with soluble CD4 before addition to coreceptor-expressing cells or will be added to murine fibroblasts expressing human CD4 and one of the two coreceptors.